Often, in the medical and veterinary programs, it is desirable and important to provide for the slow release of a beneficial agent such as a drug to the uterus at a controlled and continuous rate over a prolonged period of time. In many programs, such a rate of release should be substantially constant or have a zero order time dependence, that is, the rate of release is independent of time. For example, in contraception, it has been found that fertility can be regulated by release of the steroid progesterone to the uterus from a device inserted in the uterine lumen; with release of progesterone from the device at a constant rate for a prolonged period, a convenient long-term birth control procedure is provided.
Different approaches have heretofore been tried to obtain a delivery device for releasing drug at a controlled rate. One approach, which has received great attention, is to mix the drug with a carrier material that is gradually broken down by body fluids, the drug being released as the carrier disintegrates. Numerous carriers have been used in such systems including waxes, oils, fats, soluble polymers and the like. While some of these systems have provided for a delayed release of the drug, constant release rate has not been obtained. One reason for this is that as the carrier disintegrates the surface area of the dosage unit decreases, concomitantly exposing increasingly smaller quantities of the carrier to the surrounding body fluids. This inherently results in a decline in the release rate over time. Moreover, there has been little success in gaining control over drug release rate by this approach.
Another approach has been to enclose the drug within a capsule having polymeric walls through which the drug can pass by diffusion. An approach of this kind is set forth in U.S. Pat. No. 3,279,996. These devices too have inherent difficulties. These prior systems have generally been based on the use of silicone rubber polymers, especially polydimethylsiloxanes, as the diffusion control membrane. In large part, these silicone polymers were selected because of their high permeability to some important drug molecules. But it has now been found that this high permeability can be a significant disadvantage which defeats the primary objective of an acceptable and useful drug delivery device. Thus, with many important drug molecules, such as progesterone, the diffusion rate through polydimethylsiloxane membranes is very great, often greater than the rate of clearance of the diffused drug from the outer surface of the capsule. In many instances, this results in the rate limiting step being clearance of the drug from the exterior of the capsule, rather than diffusion through the capsule wall. Clearance rate within the body is difficult to control, as it is subject to frequent changes and, when it is the rate-limiting step, the objective of providing a drug delivery device which releases drug at a constant rate over time cannot be obtained. Also, silicone rubbers have a tendency to absorb lipoidal materials from the body. When this effect occurs in vivo, the nature of the membrane changes, altering the release rate. Still another problem with the silicone rubber dosage forms is the difficulty encountered in fabrication, attributable largely to the silicone rubber itself, that is, it is not thermoplastic and accordingly it does not lend itself to the manufacture of heat sealed drug delivery devices. While the above-mentioned polymer, silicone, has been found to have too high a permeability to many therapeutic drugs to lend itself to successful use as a drug release rate controlling barrier, in other instances, polymers such as poly(ethylene), which is thermoplastic and has a high degree of crystallinity, has also been found to have too high a melting point that can adversely affect the drug during fabrication of the device, and because its crystallinity has too low a permeability to drug to be successfully used as a drug release rate barrier.
In unrelated, non-uterine fields, polymeric materials have been used for releasing non-uterine substances. For example, in U.S. Pat. No. 3,310,235 a device is disclosed made of the material ethylene-vinyl acetate copolymer, as seemingly suitable for releasing volatile, organic and toxic phosphorous biocides by the process of physical evaporation. With this device, biocide release is achieved by evaporation from the surface, and if the ingredient is not sufficiently volatile at the temperature of use, the device has no practical value. Evaporation is achieved by using a woven cloth which acts as an evaporation surface. Release rate by evaporation is difficult to regulate and virtually impossible to control, as it is subjected to uncontrollable environmental conditions, the vapor pressure of the substance, and the degree of saturation of the volatile substance in the environment. This type of clearance inherently defeats the basic purpose of providing a device for uterine use which requires release of agent at a controlled and continuous rate for a prolonged period of time as by the process of diffusion. Other incidental and non-therapeutic uses for ethylene-vinyl acetate copolymer are disclosed in U.S. Pat. No. 3,400,011 wherein the polymeric material is mixed with waxes and used for coating ingredients that are substantially released by the movement of external fluids into the coating, causing it to rupture and release the ingredient; in French Pat. No. 1,489,490 as a thickener; and in French Pat. No. 1,505,267 as a non-diffusional formless base for chewing gum. In our U.S. Pat. No. 3,903,880 issued Sept. 9, 1975 delivery devices manufactured from ethylene-vinyl acetate copolymer are disclosed for releasing drugs at controlled rates to animals. The devices claimed in said patent are intrauterine devices and they are used for releasing agent to the uterus. In this application, it has now been found that other ethylene-vinyl ester copolymers can be inventively used for manufacturing intrauterine systems designed in the form of an intrauterine device for releasing a beneficial agent to the uterus at a controlled rate over a prolonged period of time.